The goal of this research is to determine the molecular mechanisms of transcytosis of polymeric immunoglobulins (pig), dimeric dlgA (dlgA) and, in some cases, pentameric IgM. Many epithelial cells lining exposed mucosal surfaces express the polymeric immunoglobulin receptor (plgR). The plgR is found on the basolateral surface of these epithelial cells, where it can bind to IgA. The complex of dlgA and plgR is endocytosed and carried across the cell via a series of endosomal and transcytotic compartments, which eventually fuse with the apical surface of the cell. There the extracellular domain of the plgR is proteolytically cleaved off, producing a fragment called secretorycomponent (SC). The SC is released together with its bound dlgA into external secretions, where the dlgA forms the first specific immunological barrier against infection. In yeast the retromer complex is a recently described coat protein complex that is involved in retrieval of proteins from late endosomes back to the trans-Golgi network (TGN). We found that the plgR interacts with the retromer in vivo and that the retromer is involved in promoting transcytosis of the plgR. The GGA proteins are recently discovered coat proteins that function to sort Mannose-6-Phosphate Receptors (M6PR) from the TGN to endosomes. We found that the plgR binds to GGA3, but not to GGA1 or GGA. We will test the hypothesis that the GGA3 is involved in plgR trafficking, most likely in delivery from the TGN to the basolateral surface and/or transcytosis.The exocyst is a protein complex involved in docking of exocytotic vesicles with the basolateral plasma membrane. We found that the exocyst also interacts with the translocon in the rough endoplasmic reticulum, where it regulates the synthesis of basolateral proteins, including the plgR. We will study the molecular mechanisms by which these proteins interact with the plgR and promote its transcytosis. Most infectious agents enter the body through exposed mucosal surfaces. The first specific immunological defense against these agents is the transport of immunoglobulin A (IgA) into external mucosal secretions. We are studying how IgA is transported by the polymeric immunoglobulin receptor.